Triple agonists: GLP-1, GIP, and glucagon
Adding glucagon receptor activity to incretin agonism — using a hormone long considered the opposition.
Triple agonists add glucagon receptor activity to GLP-1 and GIP agonism. The premise is initially strange: glucagon raises blood glucose, and opposing it has been a goal of diabetes therapy for decades. But glucagon also increases energy expenditure and promotes hepatic fat oxidation. In a molecule whose incretin components hold glucose in check, glucagon's metabolic effects may be recruited without its glycaemic penalty.
Emerging evidence suggests triple agonists further enhance metabolic outcomes relative to dual agonism. This remains a younger literature than that behind GLP-1 or dual agonists, and the balance of the three activities within one molecule is a fine-tuning problem that is still open.
The wider trajectory is what makes this interesting: from replacing one hormone, to combining two, to deliberately engineering the ratio of three signals in a single molecule. Whether added complexity keeps yielding benefit — and at what tolerability cost — is exactly what later-phase trials exist to determine.
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